5-hydroxy-dibenzocyclohepten-5-yl-carboxylates



United States Patent Ofiice 3,349fi93 Patented Oct. 24, 1967 3,349,093 S-HYDROXY-DIBENZOCYCLUHEPTEN- fi-YL-CARBOXYLATES Cornelis van der Stelt, Haarlem, Netherlands, assignor to N.V. Koninlrlijire Pharmaceutische Fabrieken v/h Brocades-Stheeman & Pharmacia, Amsterdam, Netherlands No Drawing. Filed Sept. 1, 1965, Ser. No. 484,420 Claims priority, application Great Britain, Oct. 31, 1964, 44,518/64 3 Claims. (Cl. 26)292) ABSTRACT OF THE DISCLOSURE This invention relates to new pharmaceutical compounds having the formula H C=O wherein X represents a CH CH or -CH=CH- group, R and R are the same or difierent and each represents a hydrogen or halogen atom or a lower alkyl group, and R represents a saturated polycyclic nitrogencontaining radical with from one to twelve carbon atoms attached through carbon to the oxygen atom, and acidaddition salts thereof.

These compounds possess anti-arythmetic and atropinelike activity.

This invention relates to new therapeutically useful esters of S-hydroxydibenzocycloheptenyl-carboxylic acids and their acid-addition salts, to processes for their preparation and to pharmaceutical preparation constaining them.

According to the present invention, there are provided the new esters of S-hydroxy-SH-dibenzocyclohepten-S- yl-carboxylic acids of the general formula:

)Rs (I) wherein X represents a CH -CH or CH=CH group, R and R are the same or different and each represents a hydrogen or halogen atom or a lower alkyl group, and R represents a saturated polycyclic nitrogencontaining radical with from one to twelve carbon atoms attached through carbon to the oxygen atom, and acidaddition salts thereof. Examples of saturated polycyclic nitrogen-containing radicals which the symbol R may represent are 3-tropanyl, N-lower alkyl-3-tropanyl, N-

ular compound and the requirements of the patient. Generally, from about 50 mg. to mg. of compound per kg. of weight may be utilized the preferred dosage being from about 5 mg. to 10 mg. per kg. of weight. When used for therapeutic purposes they may be employed as such or in the form of non-toxic acid-addition salts, -i.e., salts which are not harmful to the animal organism when used in therapeutic doses. Such salts may be derived from inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulphuric acid, nitric acid and phosphoric acid, and organic acids such as oxalic, maleic, tartaric, citric, acetic, lactic, succinic, fumaric and pamoic acids. The preferred compounds of the invention are those wherein X represents a CH -CH group, R is in the 3-position and represents a hydrogen or chlorine atom or a methyl group, R represents a hydrogen atom, and R represents a 3-tropanyl or 3-quinuclidinyl radical and their nontoxic acid-additicn salts and, in particular, the quinuclidin- 3-yl ester of 10,11-dihydro-S-hydroxy-SH-dibenzo[a,d] cyclohepten-S-carboxylic acid.

According to a feature of the invention, the compounds of Formula I are prepared by the esterification of an acid of the formula:

HO COOH (II) (wherein X, R and R are as hereinbefore defined) or a reactive derivative thereof, such as an acid halide (preferablychloride), with an alcohol of the formula R OH, R being as hereinbefore defined. The reaction can be carried out by heating the reactants in the presence of an inert organic solvent, e.g., dichloroethane, benzene, or purified light petroleum.

According to a modification of the aforesaid reaction, a halide R Y, wherein R is as hereinbefore defined and Y represents a halogen (preferably chlorine) atom, is reacted with an acid of Formula II. The reaction can be carried out by heating the reactants in an appropriate solvent such as a low boiling alcohol, e.g., isopropanol.

According to a further modification of the reaction, an acid of Formula II is first converted into an ester, preferably an ester with a lower aliphatic alcohol such as the methyl ester, and the compounds of Formula I are then obtained by transesterification, i.e., by exchange of the ester group for the group R by reaction with an alcohol R OH. The transesterification reaction is preferably carried out in the presence of sodium or sodium hydride. It is advantageous to effect the conversion in an inert organic solvent such as benzene, toluene or xylene.

The acids of Formula II can be obtained by reacting a ketone of the formula:

as starting materials are 10,1l-dihydro-SH-dibenzo[a,d] cyclohepten-5-one; 1,2,3 and 4-chloro-10,ll-dihydro-SH- dibenzo[a,d]cyclohepten-5-one; 1,2,3 and 4-bromo-10,11- dihydro-SH-dibenzo[a,d]cyclhepten-5-one; 1,2,3 and 4- methyl-10,11-dihydro-H dibenzo[a,d]cyclohepten 5- one; 1,2,3 and 4-ethyl-l0,1l-dihydro-SH-dibenzo[a,d]cyclohepten-S-one; 1,2,3 and 4-isopropyl-10,1l-dihydro-SH- dibenzo[a,d]cyclohepten-5-one; 1,2,3 and 4-t.butyl-10,1ldihydro-SH-dibeuzo[a,dJcyclohepten-S-one; 3,9-, 1,7- and 3,7-dimethyl-10,ll-dihydro 5H dibenzo[a,d]cyclohepten-5-one; SH-dibenzo[a,d]cyclohepten-5-one; 1,2,3 and 4-chloro-5H-dibenzo[a,dlcyelohepten-S-one; 1,2,3 and 4- bromo-SH-dibenzo[a,dlcyclohepten-S-one; 1,2,3 and 4- methyl-5H-dibenzo[a,d]cycIOhepten-S'one; 1,2,3 and 4- ethyl-5H-dibenzo[a,d]cyclohepten-S-one; 1,2,3 and 4-isopropyl-5H-dibenzo[a,dlcyclohepten-S-one; 1,2,3 and 4- t.butyl-5H-dibenzo[a,d]cyclohepten-5-one; 3,9-, 17 and 3,7-dimethyl 5H dibenzo[a,dlcyclohepten-S-one. The above mentioned ketones insofar as they are presently unknown can be prepared according to the procedures described in British patent specification No. 943,604.

The acid halides and esters, e.g., lower alkyl esters, of the acids of Formula II can be prepared by methods known to the art.

The compounds of the invention when prepared by the aforementioned process or its modifications in the form of the .free basic esters can be converted into corresponding acid-addition salts by a manner known to the art, e.g., by dissolving the ester in an inert anhydrous organic solvent and adding a solution of the desired acid preferably in the same or in a homogenously miscible solvent, and causing the salt to precipitate.

The following examples, in which the temperatures mentioned are in degrees centigrade, illustrate the preparation of esters of 5-hydroxy-SH-dibenzocycloheptenylcarboxylic acids of the present invention.

EXAMPLE 1 (a) To a solution of g. of quinuclidin-B-ol in 60 ml. of anhydrous benzene, 13 g. of the methyl ester of 5-hydroxy-10,1l-dihydro 5H dibenzo[a,d]cyclohepten-S-carboxylic acid and 0.4 g. of a 50% sodium hydride suspension in a mineral oil are added carefully. Transesterification of the acid is carried out azeotropically. Water with benzene is distilled off and replaced with anhydrous benzene at the same rate for about four hours. After cooling the remaining sodium hydride is decomposed by the addition of ml. of water. The aqueous layer is separated and the benzene layer is washed with water. The quinuclidin-3-yl ester of 5-hydroxy-10,11-dihydro- SH-dibenzo[a,d]cyclohepten-S-carboxylic. acid is precipitated by the additionof diethyl ether and petroleum ether (boiling range 28-40"). The ester is. filtered off and washed with Water and diethyl ether. The combined organic layers are treated with a dilute hydrochloric acid solution. The acidic aqueous solution is made alkaline and the precipitated solid yields a second crop of ester.

Total yield is 16 g. (89%) of ester product, melting atv ature drops to about 90 and the sodium, divided into small particles, becomes solid again. The mixture is cooled to room temperature and 200 g. of 10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5-one are added. The temperature is kept below 20 during the addition. Carbon diox: ide is introduced together with 500 ml. of tetrahydrofuran until the blue color disappears. Small lumps of solid carbon dioxide and water are added until all solid material is dissolved. The clear solution is concentrated under reduced pressure to about half its original volume and extracted with ether. The aqueous layer is acidified with a 2 N hydrochloricacid solution. 5-hyd'roxy-10,1l-dihydro 5H-dibenzo[a,d]cyclohepten-S-carboxylic acid precipitates and is filtered otf. Yield: 230 g. of product, melting at -190".

The methyl ester is prepared from the acid in the following way:

An ethereal solution of diazomethane is added to a solution of 5-hydroxy-10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-S-carboxylic acid in the same solvent until a yellow color persists. Excess of diazomethane is destroyed by the addition of a solution of acetic acid in ether. The solution is washed with a dilute sodium bicarbonate solution, thereafter with waterand dried with sodium sulphate. After filtration the solvent is distilled off and the residue is crystallized from carbon tetrachloride. Yield of methyl ester: g. (90%); melting point 138 140.

EXAMPLE 2 3-tr0panyl-5-hydroxy-10,1 1 -dihya' r0xy-5 H -di benze- [a,d] cycl ohepten-S -carbox y late 7.21%; N, 3.71%. Found: C, 76.42%; H, 7.08%; N,

EXAMPLE 3 Quinuclidin-3-yl-5-hydr0xy-5H-dibenz0 [a,d1cyclohepten- 5 -carboxy late (a) Following the procedure described in step (a) of Example 1 but substituting an equivalent amount of the methyl ester of 5-hydroXy-5H-dibenzo[a,d]cyclohepten- S-carboxylic acid for the methyl ester of 5-hydroxy-10,11- dihydro-5H-dibenzo[a,d] cyclohepten 5 carboxylic acid, the quinuclidin-3-yl ester of S-hydroxy-SH-dibenzo[a,d] cyclohepten-S-carboxylic acid is obtained in 66% yield. Its melting point is 257-259", and its maleate melts at 182-1 84 C.

Analysis.Calcd. for C H- O- N: C, 67.91%; H, 5.70%; N, 2.94%. Found: C, 67.9%; H, 5.8%; N, 3.1%.

(b) The methyl ester starting material is obtained in 65% yield following the procedure described in step (b) of Example 1 but substituting an equivalent amount of SH-dibenzo[a,d]cyclohepten-5-one for the 10,11-dihydro-SH-dibenzo a,d] cyclohepten-5one.

EXAMPLE 4 3-tr0panyZ-S-hydroxy-SH-dibenzo [a,d] cycloheplen-S- carboxylate Following the procedure described in step (a) of Example 1 but-substituting an equivalent amount of tropine for the quinuclidin-3-ol and the methylester of S-hydrOxy- SH-dibenzo[a,d]cyclohepten-S-carboxylic acid for the methyl ester of 10,11 dihydro 5 hydroxy-SH-dibenzo [a,d]cyclohepten-S-carboxylic acid, the 3-tropanyl ester of 5 hydroxy-SI-Ldibenzo[a,d]cyclohepten-S-carboxylic acid is obtained in 30% yield. Melting point 248-250.

Analysis.-Calcd. for C H NO C, 76.76%; H, 6.71%; N, 3.74%. Found: C, 76.40%; H, 6.59%; N, 4.00%.

Similarly, if an R and/ or R -substituted 10,11-dihydro- S-hydr-oxy-SH-dibenzo [a,d] cyclohepten-S-carboxylic acid alkyl ester is substituted for the 10,11-dihydro-5-hydroxy- 5Hdibenzo[a,d] cyclohepten 5 carboxylic acid methyl ester in Example 1, the corresponding quinuclidin-3-yl ester of the R and/or R substituted-10,1l-dihydro-S- hydroxy-5Hdibenzo[a,d]cyclohepten-S-carboxylic acid is obtained. Moreover, if an R and/or R substituted 5- hydroxy-SH-dibenzo [a,d] cyclohepten 5 carboxylic acid alkyl ester is substituted for the S-hydroxy-SH-dibenzo [a,d]cyclohepten-S-carboXylic acid methyl ester in EX- ample 1, the corresponding quinuclidin-3-yl ester of the R and/or R substituted-5-hydroxy-5H-dibenzo[a,d]cyclohepten-S-carboxylic acid is obtained.

The invention includes within its scope pharmaceutical preparations containing, as the active ingredient, at least one of the therapeutically active compounds of general Formula I, or non-toxic acid-addition salt thereof, in association with a pharmaceutically-acceptable carrier. The preparations may take any of the forms customarily employed for administration of therapeutically active substances, but the preferred types are those suitable for oral administration and especially tablets, including sustained release tablets, pills and capsules including the substance. The tablets and pills may be formulated in the usual manner with one or more pharmaceutically-acceptable diluents or excipients, for example, lactose or starch, and include materials of a lubricating nature, for example, calcium or magnesium stearate. Capsules made of absorbable material, such as gelatin, may contain the active substance alone or in admixture with a solid or liquid diluent. Liquid preparations may be in the form of suspensions, emulsions, syrups or elixirs of the active substance in water or other liquid medium commonly used for making orally acceptable pharmaceutical formulations, such as liquid paraffin, or a syrup or elixir base. The active substance may also be made up in a form for arenteral administration, i.e., as a suspension or emulsion in sterile Water 'or an organic liquid usually employed for injectable preparations, for example, a vegetable oil such as olive oil, or a sterile solution in an organic solvent.

While there have been described various embodiments wherein X is selected from the group consisting of CH -CH and -CH=CH, R and R are selected from the group consisting of hydrogen, halogen, and lower alkyl, and R is a tro ane attached through carbon to the oxygen atom, and acid-addition salts thereof.

2. 3 tropanyl-5-hydroxy-10,1l-dihydroxy-SH-dibenzm [a,d]cyclohepten-S-carboxylate.

3. 3 tropanyl-S-hydroxy-5H-dibenzo[a,d] cyclohepten- S-carboxylate.

References Cited UNITED STATES PATENTS 3,264,308 8/1966 Van der Stelt 260-292 WALTER A. MODANCE, Primary Examiner. A. L. ROTMAN, Assistant Examiner. 

1. A COMPOUND HAVING THE FORMULA 